Insect repellents are used globally as a means of reducing human-insect vector contact, thereby minimizing the incidence of vector-borne disease transmission as well as the general discomfort associated with insect bites. The best known and most widely used active ingredient in commercial topical insect repellents is the synthetic benzene derivative, N,N-diethyltoluamide (DEET).
Nepetalactone (represented in general by schematic Formula X),
is a major component of an essential oil secreted by plants of the genus Nepeta and the active ingredient in catnip, and is known to be an effective, natural repellent to a variety of insects [Eisner, T., Science (1964) 146:1318-1320]. U.S. Pat. No. 6,524,605 discloses the repellency of nepetalactone, as well as the individual cis,trans (Z,E) and trans,cis (E,Z) isomers, against German cockroaches.
Dihydronepetalactone (DHN), represented in general by schematic Formula I,
is a chemical which is secreted by certain insects, and is known to exhibit insect repellency activity. Jefson et al [J. Chemical Ecology (1983) 9:159-180] described the repellent effect of DHN on feeding by ants of the species Monomorium destructor. More recently, Hallahan (WO 03/79786) has found that DHN compares favorably as an insect repellent with DEET.
Dawson et al have described a method of preparing the ethyl acetal of nepetalic acid from carvone in a seven step procedure as set forth in “The Aphid Sex Pheromone Cyclopentanoids Synthesis in the Elucidation of Structure and Biosynthetic Pathways” in Bioorganic & Medicinal Chemistry 4(3): 351-361 (1996) as shown below in Table 1. The compounds made by this process have the R configuration at the methyl-bearing carbon on the cyclopentyl ring.
TABLE 1Synthesis of ethyl acetal of nepetalic acid(i) (a) Br2; (b) NaOMe, MeOH; (c) aq KOH, heat;(ii) ButOK, DMF, 140° C., 3 h;(iii) CH2N2;(iv) (a) diisoamylborane; (b) NaOH, H2O2;(v) PCC;(vi) HC(OEt)3; TsOH, EtOH;(vii) KOH, aq EtOH;(viii) 100° C.;(ix) 300° C.
Despite the previous work as described above, a need remains for the continued availability of as wide a variety of insect repellents as possible, and the novel acetals described herein have been found to be useful as repellents for insects and arthropods, as well as for other purposes.